Conservative surgery with axillary dissection and supplementary radiotherapy is the treatment of choice in patients with small-sized breast cancers. The results of recent clinical trials, particularly randomised trials (U. Veronesi, et al., New Engl. J. Med., 305:6-11, 1981; U. Veronesi, et al., Ann. Surg. Vol. 211, 3:250-259, 1990), have shown that the risk of local recurrence of the tumour correlates with the extent of the operation on the breast, with the patient's age, and with the presence of an extensive intraductal component and peritumoral lymphatic and/or vascular invasion. In addition, a reduced incidence of local recurrence has been demonstrated in subjects undergoing supplementary radiotherapy (5.4% as against 21.6% in the control group).
The supplementary external radiotherapy currently used after surgical quadrantectomy involves the administration of a total dose of 50-60 Gy in 6 weeks of treatment, with irradiation of the entire residual breast after surgery and optionally an overdose on the operative bed. This kind of treatment regimen has by no means negligible psychological implications; its long duration increases and prolongs the patient's state of anxiety related to her experience of the disease and leads her to believe that the surgical operation has not been successful in resolving the disease. Moreover, there is also a by no means negligible social impact in terms of costs, related to the patient's absence off work for a period of about 2 months.
As an alternative to traditional radiotherapy treatment Intraoperative Radiotherapy (IORT) has recently been proposed, which is a radiotherapy technique that makes it possible to deliver a single dose of radiation directly to the tumour exposed during surgery, or to the anatomical area that contained the tumour after surgical removal of the cancer. The inventors of the present invention have used IORT with satisfactory results in the context of a randomised study for the treatment of stage T1 cancer of the breast. From the logistic point of view, however, only in a very few centres is it possible to implement this type of therapy; the cost of the equipment alone is more than one million euros, without considering the architectural costs of constructing a shielded operating theatre to guarantee radioprotection for the operators and people in the adjacent rooms and of the specialist staff necessary for implementing the treatment.
A radioimmunotherapy protocol called three-step radioimmunotherapy is known, the details of which are described in the European Journal of Nuclear Medicament Vol. 26, No. 2, February 1999, pp. 110-120 e No. 4, April 1999, pp. 348-357 and in European Patent EP 0 496 074. In this method, a reagent kit is used in a form suitable for intravenous administration, consisting of 1) a biotinylated monoclonal antibody specific for an antigen associated with a tumour, 2) a protein of the avidin type, 3) biotin or one of its derivatives conjugated with an efficacious agent for the treatment and/or diagnosis of a tumour. Useful agents for reducing the circulating levels of biotinylated antibody and of proteins of the avidin family (chasing agents) have also been described in the three-step radioimmunotherapy method. Such kits are indicated for intracavitary or systemic administration, but no suggestions are provided with regard to sequential administration including both the surgical act and postoperative systemic treatment.
The three-step method is undoubtedly valid in its general description, but it can be optimised and further exploited if large amounts of avidin are introduced onto the tumour or in areas of the body which could receive or which already harbour residual tumour cells after an apparently radical operation. The two main limitations of the classic three-step method consist in the fact that only modest amounts of antibodies and proteins of the avidin family, —most frequently streptavidin (steps 1 and 2)—reach the target after intravenous inoculation. The locoregional inoculation is applicable in natural anatomical cavities such as the peritoneum, pleura, or bladder, or in postoperative virtual cavities as in the case of brain tumours.